The Microbiome / Immune Connection

Table of Contents

Intro

Now that you have an understanding of how important the microbiome can be in generating health, or conversely disease, we need to dive into some of the mechanisms by which that happens.

First up is the immune system and the connection between the microbiome and inflammatory disease. Approximately 75% of your entire immune system resides in your gut, which just goes to show how important this connection truly is. In Lecture 3 we’ll go through the mechanisms through which the immune system “sees” the microbiome, and how the immune system is shaped by microbiome.

We’ll discuss the critical role of short chain fatty acids, produced by the microbiome, and how they impact the immune system. Specifically we’ll cover how SCFAs are formed, how they alter various tissues in the gut that are critical for barrier function, and how they generate a tolerogenic environment.

Finally, we’ll discuss what “Leaky Gut” truly is and what drives it to happen in the first place. We’ll explore the role of dysbiosis in this process and examine the connection to autoimmunity at distal sites.

Key understandings

  • Understand what tools the immune system uses to “see” the microbiome
  • Understand that the microbiome drives the maturation of the immune system early in life
  • Explain how the immune system constrains and shapes the Microbiome
  • Understand what oral tolerance is and how the microbiome contributes to this
  • Be able to explain how resistant starch is used to create short chain fatty acids
  • Understand how butyrate impacts the immune system, the gut barrier and cancerous cells
  • Define dysbiosis
  • List several factors that can cause dysbiosis
  • Define Leaky gut

Gut Biology Key Terms

  • Pattern recognition receptors
  • Pathogen-associated molecular patterns
  • Antibodies
  • Immunoglobulin A (IgA)
  • Mucus
  • Oral tolerance
  • Short chain fatty acids
  • Butyrate
  • Resistant Starch
  • Regulatory T cell
  • Dysbiosis
  • Leaky gut

Lecture

Microbiome and immune system are in constant communication together

  • The microbiome is necessary for optimal development and function of the immune system without the microbiome, the immune system is lacking

  • Despite its benefits, the immune system works to keep the microbiome from infiltrating into the host tissue. Need to control the microbiome. Needs to stay in the Lumen

  • A healthy microbiome contributes to a tolerogenic environment, but dysbiosis is associated, and causes disease.

You don’t want aggressive immune responsizes to every event. You’d be pissed off and inflamed the whole time

How the Immune System ’sees’ bacteria

Pattern recognition receptors

  • LPS: repetitive structure of your cell wall that signals to your immune cell that an action needs to be taken

  • Antibodies: B cells, most importantly igA. They bind bad bacteria and renders them useless so they just pass. Another way that the body sees bacteria

  • Lymph nodes: places where B cells live

Microbiome-immune drives formation of the immune system

  • Much of the immune system is under-developed in germ free mice
  • Decreased innate immune function of monocytes, macrophages and neutrophils
  • Decreased adaptive immune responses with T and B cells

The composition of the microbiome directly impacts what type of cells are created in you immune system

Microbiome induces protective mucus production

germ-free mice have less of this mucus in their gut

  • This mucus layer provides compartmentalization of bacteria in the gut
  • Specific antimicrobial peptides are secreted into the mucus to eliminate pathogenic bacteria epitherial layer has ability to produce molecules that kill baceria
  • igA antibodies are also secreted to eliminate bacteria that come into contact
  • People who are deficient in IgA have more inflammatory bacteria

Mucus provides physical barrier of most bacteria

The GI Immune System is a Tolerogenic Environment

  • “Tolerance” is the active process of shutting down immune responses against non–pathogenic antigens genetically programmed response. not harmful antigens… food you eat, bacteria that lives in your gut only want immune responses to pro-inflammatory bacteria

  • We do NOT want to make aggressive immune responses against everything that we eat, nor the bacteria that live in our gut

  • Normal components of the microbiome trigger the INHIBITION of inflammation

  • Several products produced by bacteria induce suppressive T cells called Tregs

Short chain fatty acids (SCFAs) and Microbiome Biology

  • Bacterial fermentation byproducts derived from resistant starch as a fuel source (potatoes)
  • Acetate, propionate, and butyrate are the most studied biologically
  • Found in high concentrations in the digestive tract
  • Play an integral role in intestinal homeostasis and preventing disease
  • Altered levels of SCFA are associated with IBD, obesity, and neurological disease

Generation of SCFAs

  • Humans have a suite of amylases and amyloglucosidases to break starches into glucose
  • However, some starches, termed resistant starch are able to escape digestion and reach the colon where they are fermented by certain specialized microorganisms

There are quite a few types of resistant starch.. RSI, RSII, RSIII, RSIV, RSV

Respectively: unmilled seeds; uncooked potato, corn, green-banana flours; potato salad; Fibersym RW; Fried rice

Different bacteria use the starch source as fuel, then other bacteria consume that byproduct as fuel, and then other bacteria use THAT byproduct as fuel –> which all of this produce short chain fatty acids

Butyrate

Used to create ATP.

  • Germ free mice have colonocytes that are “energy deprived”

    • The administration of free butyrate restores their health and function

  • While butyrate enhances the proliferation of healthy gut tissue, it INHIBITS the growth of cancerous epithelium, limiting colon cancer

  • Butyrate induced the production of antimicrobial peptides by epithelial cells as well

  • Butyrate also induces the production of the cytokine IL-18, a key cytokine for the repair and maintenance of epithelial integrity

  • “Calm” the proinflammatory nature of neutrophils, monocytes and macrophages

  • Induce a “tolerance” promoting T cell phenotype called regulatory T cells

  • Impairs the generation of Th2 T cells which are responsible for food allergies

Clinical Uses of Butyrate/Resistant Starch

  • As early as the 1980s, SCFAs were observed to offer therapeutic benefit in some forms of colitis
  • A 1992 study showed that 10 patients with ulcerative colitis, given a butyrate enema had decreased inflammation and bleeding
  • Resistant and/or butyrate starch improved recovery times in people suffering from diarrhea

What happens when the bacteria go bad?

It’s called dysbiosis

causes of dysbiosis

  • Can be caused by a multitude of factors

    • Diet
    • Antibiotics
    • Exposure to chemicals
    • Genetics
    • Infection

  • Different “imbalances” have been associated with multiple inflammatory diseases

  • Determining what is a cause and what is an effect is difficult but several mechanisms can be at play

affects the barrier defense of your intestinal epithelial cell

T cell dysfunction

Th-17 cells have been linked to auto-immune diseases when there are too many in your body/ in the wrong places. Even if they help the epithelial cell wall

What is Leaky gut?

Dysbiosis can cause leaky gut.

A combination of immune defects and microbial changes that result in poor barrier function in the GI tract As a result, bacteria and bacterial products translocate through the mucus layer into the gut tissue, causing substantial inflammation LPS and other bacterial products can be detected in the blood stream and in distal organs

Rheumatoid Arthritis and the Microbiome

  • RA is an autoimmune disease where the immune system is attacking the tissue in the joints
  • Dysbiosis is detected in the gut and oral microbiomes of RA patients
  • Alterations in the gut, dental or saliva microbiome distinguish RA patients from healthy controls, and could be used to stratify individuals on their response to therapy
  • Microbiome transplantation from RA patients recapitulated disease in germ free mice

Does the microbiome cause RA?

  • It’s more complicated than that

Environmental factors (tiggers) smoking, hormones, microbiota

Genetics

You likely need to hit 3 triggers to develop RA

microbiome layered on top of genetics, layered on top of the environment you are in.

Inflammation from the immune system drives outgrowth of specific bateria

Summary

This week’s supplemental video focuses on how inflammation from the immune system actually drives the outgrowth of specific bacteria in the gut and what the consequence of this is for the host (dysbiosis).

It’s really fascinating to think about the back and forth dance between the host, the microbiome, and then other factors that cause perturbations (such as infection).

Lecture

infected mice with a parasite that causes a large immune response from the host (and drives inflammation)

Proteobacteria bacteria dominates the composition after infection. (ecoli is one of those)

Total amount of bacteria increases substantially as well

Does resolve over time.

What mechanism drives this?

Conditions of inflamation in the large bowel show an outgrowth of E. coli and a reduction of regular microbes in the microbiome

nitric oxide and inducivible nitric oxide synthase are both present in large quantities during inflamation. E. coli can use these compounds for growth

Cyclical feedback loop of immune system is being shaped by the microbiome, activated by some trigger, producing some chemicals which alters the microbiome which changes the comp of the immune syste,

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